Identification of a neutrophil-related gene expression signature that is enriched in adult systemic lupus erythematosus patients with active nephritis: Clinical/pathologic associations and etiologic mechanisms

Abstract

Both a lack of biomarkers and relatively ineffective treatments constitute impediments to management of lupus nephritis (LN). Here we used gene expression microarrays to contrast the transcriptomic profiles of active SLE patients with and without LN to identify potential biomarkers for this condition. RNA isolated from whole peripheral blood of active SLE patients was used for transcriptomic profiling and the data analyzed by linear modeling, with corrections for multiple testing. Results were validated in a second cohort of SLE patients, using NanoString technology. The majority of genes demonstrating altered transcript abundance between patients with and without LN were neutrophil-related. Findings in the validation cohort confirmed this observation and showed that levels of RNA abundance in renal remission were similar to active patients without LN. In secondary analyses, RNA abundance correlated with disease activity, hematuria and proteinuria, but not renal biopsy changes. As abundance levels of the individual transcripts correlated strongly with each other, a composite neutrophil score was generated by summing all levels before examining additional correlations. There was a modest correlation between the neutrophil score and the blood neutrophil count, which was largely driven by the dose of glucocorticosteroids and not the proportion of low density and/or activated neutrophils. Analysis of longitudinal data revealed no correlation between baseline neutrophil score or changes over the first year of follow-up with subsequent renal flare or treatment outcomes, respectively. The findings argue that although the neutrophil score is associated with LN, its clinical utility as a biomarker may be limited.

Neutrophil Extracellular Traps (NETs) Promote Pro-Metastatic Phenotype in Human Breast Cancer Cells through Epithelial–Mesenchymal Transition

“…For this purpose, we first analyzed a set of genes defined as a neutrophil-related signature in the different breast cancer subtypes. These neutrophil-related genes ( MPO , DEFA1B , MMP8 , CEACAM8 , LTF , and DEFA4 ) were identified and evaluated in a previous study [ 39 ]. The MPO gene encodes myeloperoxidase, an abundant enzyme in the neutrophil azurophilic granules, which has microbicidal activity through the generation of hypochlorous acid [ 40 ].…”

Neutrophils Mediate Kidney Inflammation Following Acute Skin Exposure to UVB Light

“…The role of IL17A in regulating granulopoiesis and neutrophil recruitment via induction of G-CSF is well recognized under homeostatic conditions 34,70 and a few studies have identified IL17-A as important for neutrophil recruitment to the sites of sterile inflammation 71,72 . In lupus, elevated IL-17A expression is found in cutaneous lesions 73,74 and increased circulating IL-17A levels have been associated with worse disease manifestations 75,76 , although the specific relationship to neutrophils, a pathogenic population in this disease, 11,[15][16][17] remains unexplored. Besides its direct effects on G-CSF-mediated mobilization of neutrophils from the bone marrow, IL-17A may also contribute to neutrophil homing to the kidney by stimulating expression of adhesion molecules (e.g.…”

“…Neutrophils can also promote tissue repair by phagocytosis of cellular debris and by enabling tissue revascularization 50 . In SLE, a neutrophil gene signature is a strong predictor of active disease including LN and cutaneous lupus [15][16][17] . Neutrophils are found in cutaneous lesions [10][11][12] as well as kidney biopsy specimens 13,14 of SLE patients and their inflammatory properties have been attributed to NET formation 14,21 .…”

“…While both the aged (CXCR4 hi ) and the reverse migrating (ICAM1 hi CXCR1 lo ) neutrophil phenotypes have been associated with inflammatory functions and tissue injury in different murine models 51,52,60 , few studies have been performed on these cell populations in human disease. Given the emerging role of neutrophils in SLE 11,[15][16][17] and their apparent heterogeneity 18 , we investigated whether PMNs or low density granulocytes (LDGs) 64,65 from SLE patients demonstrated the phenotypes of aged, CXCR4 hi , or reverse migrating, ICAM1 hi CXCR1 lo , neutrophils. Flow cytometry profiling of PMNs and LDGs revealed higher CXCR4 expression on the surface of these cells in SLE patients, compared to healthy controls ( Fig.…”

“…Neutrophils are present in the skin lesions of SLE patients [10][11][12] as well as in the kidney tissue of patients with LN 13,14 . High expression of a neutrophil gene signature is a strong predictor of active SLE, including nephritis and cutaneous flares [15][16][17] . A specific subset of proinflammatory low-density granulocytes (LDGs) are increased in SLE, particularly in patients with skin disease 18 .…”